Origins of Selectivity in Brønsted Acid-Promoted Diazoalkane−Azomethine Reactions (The Aza-Darzens Aziridine Synthesis)

Troyer, Timothy L.; Muchalski, Hubert; Hong, Ki Bum; Johnston, Jeffrey N.

doi:10.1021/ol200313m

Cited by 32 publications

(21 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7,8,9,10,11 However, there is little evidence in the literature with regard to the existence of the diazonium ion intermediate or the identity of rate-limiting step in this mechanism. 7b,11 Based on our experimental KIEs, we propose that reversible formation of the catalyst bound diazonium ion intermediate ( gauche 3a’/anti 3a ’) could be followed by an irreversible S N 2-like ring-closure step (rate-limiting step) to form the aziridine with concomitant elimination of N 2 (Scheme 4). At the transition state for this step, C2 would have bond order to both the intramolecular nucleophile and the leaving group which are in an antiperiplanar orientation ( anti 3a ’).…”

Section: Resultsmentioning

confidence: 99%

“…The intermediacy of 3 has been proposed for aziridine forming reaction of imines and diazo compounds that are mediated by both Lewis and Brønsted acids 7,8,9,10 and some indirect evidence for the intermediacy of 3 has been presented in certain reactions. 11 …”

Section: Introductionmentioning

confidence: 99%

“…This assumption was a reasonable one, since the entropically favored intramolecular ring closure step that follows diazonium ion formation is expected to be facile. Although this mechanism has been suggested as the most reasonable possibility, 7b,11 it has not been addressed experimentally in any related aziridination reaction. The >50:1 cis : trans ratio was explained on the basis of the lower energy of the transition state for the carbon-carbon bond formation along the cis -pathway.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted Acid Catalyzed Aziridination Reaction

2013

View full text Add to dashboard Cite

The mechanism of the chiral VANOL-BOROX Brønsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring-closure to form the cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative energies of the ring closing transition structures.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted Acid Catalyzed Aziridination Reaction

2013

View full text Add to dashboard Cite

show abstract

“…61 , see Path A). The importance of the latter, from a reaction kinetics and enantioselectivity point of view has been established by the reluctance of these intermediates to undergo a retro‐Mannich reaction . Generating, presumed, kinetic product 61 with excellent enantioselectivity is possible only if 7 , with its heterotopic faces that is, 7 Re and 7 Si , efficiently discriminates between the Si and Re faces of optically active 60 .…”

Section: Methodsmentioning

confidence: 99%

Chiral Brønsted Acid‐Catalyzed Asymmetric Synthesis of N‐Aryl‐cis‐aziridine Carboxylate Esters

et al. 2017

View full text Add to dashboard Cite

We report amulti-component asymmetric Brønsted acid-catalyzed aza-Darzens reaction whichi sn ot limited to specific aromatic or heterocyclic aldehydes.I ncorporating alkyld iazoacetates and, important for high ees, ortho-tertbutoxyaniline our optimized reaction (i.e.solvent, temperature and catalyst study) affords excellent yields (61-98 %) and mostly > 90 %o ptically active cis-aziridines.( + +)-Chloramphenicol was generated in 4s teps from commercial starting materials.Atentative mechanism is outlined.Such is the versatility of organocatalysis and its ability to mediate ap lethora of diverse reaction types [1] it is,n ow,a n indispensable "tool" in the synthetic chemists "toolbox". [2] Indeed, improving atom-and reaction-efficiencyi sakey driver to developing new reactions and protocols;i nt his context organocatalysis has demonstrated its importance by efficiently mediating many different convergent reactions or multi-component syntheses.T he work here supports these aspects by generating structure and function-diverse motifs via fewer synthetic, isolation and purification steps.Optically active aziridines have many diverse uses, especially as key intermediates [3] "on route" to important "secondary" products for example, a-/b-amino acids,p olymers,azasugars,auxilaries,oxazolidinones,imidazolidines, blactams and pyrrolidines.F urther applications include synthesis of non-aziridine containing bioactive compounds for example,k ainoids,( À)-mesembrine,( À)-platynesine,a ctinomycin and feldamycin, in addition to synthetic bioactive aziridines for example,NSC676892 as well as natural products for example,azinomycin and maduropeptide. [4] Using aB INOL N-triflylphosphoramide Brønsted acid a6 1-98 %y ielding asymmetric aza-Darzens reaction affords N-aryl-cis-aziridines in, mostly,9 0-99 % ee.T he reaction is straightforward to set up and has minimal requirements for strictly anhydrous or anaerobic conditions,f urthermore it does not require organocatalyst pre-generation or activation, or an "activated" arylglyoxal starting material. Exploiting the protocol synthesis of aziridines based on 4 uses readily generated or commercially available aldehydes (1), amines (2)a nd alkyl diazoacetates (3,Scheme 1).Activating the C = Nb ond of an imine with aB INOL phosphoric acid [5] lowers its LUMO energy and generates an imminium ion pair that can, but not always will, react with an ucleophile.S eminal work by Akiyama et al. established chiral BINOL phosphoric acids [pK a % 13 (CH 3 CN) [6] ]a ctivate aldimines (derived from, specifically,arylglyoxals and panisidine) and react with ethyl diazoacetate (EDA) affording cis-aziridines in 92-97 % ee.[7] Similarly,o ther Brønsted acids [8] and pyridinium triflate activate ad iverse array of imines,i ncluding for example,2 -pyridyl derived 5,e nabling the presumed imminium ion-pair (not shown) to react with EDAa nd afford cis-rac-aziridine (8,8 3% yield) (Scheme 2).[9] With these racemic studies complete our focus shifted to developing asubstrate enhanced and diverse, mult...

show abstract

“…61 , see Path A). The importance of the latter, from a reaction kinetics and enantioselectivity point of view has been established by the reluctance of these intermediates to undergo a retro‐Mannich reaction 20. Generating, presumed, kinetic product 61 with excellent enantioselectivity is possible only if 7 , with its heterotopic faces that is, 7 Re and 7 Si , efficiently discriminates between the Si and Re faces of optically active 60 .…”

mentioning

confidence: 99%

Chiral Brønsted Acid‐Catalyzed Asymmetric Synthesis of N‐Aryl‐cis‐aziridine Carboxylate Esters

et al. 2017

View full text Add to dashboard Cite

We report a multi‐component asymmetric Brønsted acid‐catalyzed aza‐Darzens reaction which is not limited to specific aromatic or heterocyclic aldehydes. Incorporating alkyl diazoacetates and, important for high ee's, ortho‐tert‐butoxyaniline our optimized reaction (i.e. solvent, temperature and catalyst study) affords excellent yields (61–98 %) and mostly >90 % optically active cis‐aziridines. (+)‐Chloramphenicol was generated in 4 steps from commercial starting materials. A tentative mechanism is outlined.

show abstract

Origins of Selectivity in Brønsted Acid-Promoted Diazoalkane−Azomethine Reactions (The Aza-Darzens Aziridine Synthesis)

Cited by 32 publications

References 44 publications

Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted Acid Catalyzed Aziridination Reaction

Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted Acid Catalyzed Aziridination Reaction

Chiral Brønsted Acid‐Catalyzed Asymmetric Synthesis of N‐Aryl‐cis‐aziridine Carboxylate Esters

Chiral Brønsted Acid‐Catalyzed Asymmetric Synthesis of N‐Aryl‐cis‐aziridine Carboxylate Esters

Contact Info

Product

Resources

About